The long term goals of this multidisciplinary research are to develop more systematic, rational approaches to the design of potent receptor/acceptor selective peptide and peptidomimetic ligands for hormone and neurotransmitter receptors. We seek to obtain a fundamental understanding of the chemical/physical basis for information transfer by peptide hormones and neurotransmitters and how these chemical messengers modulate and control cellular function. Such an understanding is critical to the development of tools for understanding hormone and neurotransmitter function in normal and disease states, and for the development of effective drugs with little or no toxic side effects. The development arid use of methods for conformational and topographical constraints compatible with high potency and receptor selectivity are of critical importance to this research. This research requires a highly multidisciplinary approach including computer assisted modeling, conformational analysis using 2D NMR spectroscopy and other biophysical methods, molecular mechanics calculations and molecular dynamics simulations, asymmetric synthetic methods, macrocyclic peptide and peptidomimetic synthetic methods, evaluation of conformation-biological activity relationships, and utilization of cloned receptors to obtain potent, receptor selective peptides and peptidomimetics with specific biological properties. The primary focus of this research will be on design of agonists and antagonists for the melanocortin receptors. Specific aims include the following: 1) to develop and use asymmetric synthetic methodology, macrocyclic synthesis methodology, and other synthetic and analytical methods needed for the design of agonist and antagonist peptides and peptidomimetics; 2) to probe with specific hypotheses using conformational/topographical constraint the conformational and stereostructural requirements for obtaining stable, potent, receptor specific, prolonged acting agonists and antagonists of alpha-melanotropin for the MC1, MC3, MC4, and MC5 receptors; 3) design of specific ligands to test models of the binding interaction between alpha-melanotropins agonists and the human melanocortin 1 receptor. This model will be examined further for binding of antagonist analogues to determine the similarities and differences of agonist and antagonist binding. Site specific mutagenesis will be used to further test these models; 4) to develop receptor selective melanotropin antagonists for each of the four cloned melanocortin receptors; 5) to continue to develop and utilize computer assisted modeling, molecular mechanics and quantum mechanics calculations, 1D, 2D and 3D NMR spectroscopy, and other biophysical methods needed to examine the structural, conformational, topographical and dynamic properties of the hormones as they relate to their biological activities. All insights developed will be tested by specific design. The long term goals are to apply these methods to determine the conformation of agonists and antagonists at cloned receptors, and to provide unique ligands for evaluating and determining the physiological significance of these receptors.